DESCRIPTION: (Applicant's Description) Estrogen plays an important role in the development of the normal breast and in breast cancer. The biochemical mechanisms underlying these processes, however, are largely unknown. The goal of this proposal is to build on recent advances in the molecular understanding of estrogen receptor (ER) action to better define the role played by estrogen in the normal breast and in breast cancer. Over the past few years several important coregulatory molecules that play a central role in mediating the transcriptional activity of ER have been identified by several labs including our own. The gene encoding one of these ER coactivators, AIB1, was cloned as a gene Amplified In Breast cancer raising the possibility that altered expression of an ER coactivator may play a central role in estrogen-stimulated breast cancer growth. The central hypothesis to be addressed by this proposal is that the growth-stimulatory property of estrogen in breast cancer represents the abnormal expression or functioning of components of the normal estrogen signalling pathway. These may include ER alpha, ER beta, or ER coregulators. Preliminary studies from many laboratories including our own have demonstrated that these molecules are differentially expressed in a variety of breast cancer cell lines and primary tumors. In this proposal we will characterize the expression of the estrogen signalling machinery during normal breast development in order to be able to define those factors abnormally expressed in breast cancer. Determination of the abnormal expression of these factors in breast cancer will allow us to generate specific hypotheses concerning which components may play a role the growth-stimulatory property of estrogen in breast cancer. We will directly test these hypotheses in mammary epithelial cells and transgenic mice. These studies will be significantly facilitated through a close collaboration with the Weinberg Lab. Taken together these studies will provide a better understanding of the role played by alterations in estrogen signalling in breast cancer. Identification of those factors which are markers for these changes are likely to lead to the development of better diagnostic and prognostic tools. More importantly, the identification of the factors which are the critical regulators of the alterations in estrogen signalling will become new therapeutic targets and may lead to the development of improved strategies for the prevention and treatment of breast cancer.